The complement system is a major component of innate immunity and is linked to both the activation and effector arms of acquired immunity. In addition, recent studies have shown that certain complement components and their receptors play important in vivo roles in the maintenance of tolerance to self antigens. Complement activation fragments also amplify local inflammatory tissue injury initiated by invading phagocytes, cells believed to play key roles in promoting beta cell injury and diabetes. Several technical advances in the ability to block or otherwise manipulate complement activities in mice in vivo using therapeutically relevant strategies have been recently made by the laboratory of the PI and others. Because of this, the contribution of the complement system to beta cell damage can be readily measured using well-established mouse models such as NOD. This Basic Research Component proposal will address two primary hypotheses: 1) Complement receptors type 2 (CR2) and type 1 (CR1) play a central role in regulating self tolerance and the development of beta cell autoimmunity, insulitis and diabetes, and 2) Pro-inflammatory complement activation products promote beta cell injury and the development of diabetes. To address these hypotheses, two specific aims will be pursued: Specific Aim #1: Determine the contribution of complement receptors CR2 and CR1 to the development of beta cell injury and diabetes in NOD mice. Specific Aim #2: Determine the ability of complement inhibitors targeted at C3 activation steps to block the development of beta cell injury and diabetes in NOD mice. We believe that these are particularly relevant studies to pursue because therapeutic agents which block complement receptor function as well as the generation of complement pathway pro-inflammatory mediators are currently being developed for human use. If pre-clinical results using the approaches we are proposing are promising, the potentially beneficial effects of these agents could be assessed in individuals who are developing autoimmune diabetes and beta cell failure.